University of Virginia Health System

Tolerance and Autoimmunity: My laboratory explores the fundamental mechanisms of prevention and induction of autoimmune disease of clinical relevance. We study four major topics in autoimmune disease models. First, regulatory T cells bearing CD25 have the critical role of autoimmune disease prevention in normal adults. Their depletion leads to of autoimmune disease triggered by endogenous antigens. We now discovered that regional lymph nodes of normal mice accumulate highly active Treg that suppress autoimmunity in the organ draining to it. Thus endogenous Ag clearly maintains tolerance by stimulating Ag specific Treg in strategic locations. Whether the Treg in normal mice maintain tolerance by preventing autoimmune disease induction triggered by endogenous danger signal is being studied in unilaterally-vasectomized mice.  Second, we discovered that maternal autoantibody, nonpathogenic in adults, induces de novo pathogenic T cell response in the progeny within the first 5 days of life, leading to severe neonatal autoimmunity. The neonatal susceptibility to autoimmune disease is explained by the functional supremacy of neonatal NK cell and FcgRIII+ cells over adult counterparts. Third, we are studying spontaneous autoimmune disease in two transgenic mice expressing different levels (x40) of ovalbumin in testis germ cell autoantigen after puberty. The disease is mediated by ovalbumin specific T cells that can be visualized. Studies on these mice have provide new information on mechanism of disease induction and progression that clearly involve Treg, Th17 and Th1 effector cells, and perhaps the response of Toll like receptors to endogenous TLR ligand.

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